ABSTRACT ? Project 4:Clinical interventions & gene-by-stress effects on cardiometabolic endophenotypes For decades, our combined research groups (Williams, Kraus, Blumenthal, Jiang) have investigated the effects of psychological stress on cardiovascular disease, and the effects of exercise training, stress reduction and pharmacologic interventions to modify stress effects on cardiometabolic risk. Drs. Blumenthal's and Jiang's group has been a leader in intervention studies. Dr. Williams' group has been a leader in attempts to understand how genetic variation can modify these effects and potentially explain variations in the effectiveness of lifestyle interventions on cardiovascular outcomes. For example, they have described how BDNF, EBF1, DRD2, 5HTR2C each have specific gene-by-stress effects modified by other demographic characteristics that are associated with cardiometabolic phenotypes. However, these effects have been described primarily using cross-sectional associations in large datasets in studies that were not designed to investigate intervention effects on these relations. To move the field forward scientifically and to begin to develop effective clinical interventions to modify the adverse gene-by-stress interactions that we have identified, we will need to understand whether established lifestyle, behavioral and pharmacologic interventions can equally affect favorable cardiometabolic effects irrespective of these genetic effects, and conversely, whether the described gene-by-stress interactions affect the influence of established lifestyle, behavioral and pharmacologic interventions on cardiometabolic health. A number of important questions remain largely or totally unexplored in the field. 1) Do clinical interventions designed to target cardiometabolic risk modify or mollify the adverse gene-by-stress interactions being illuminated in Projects 1 and 2? 2) Do genes, chronic stress, or gene-by-stress effects predict who will adhere to favorable clinical interventions that favorably influence cardiometabolic health? 3) Can one demonstrate clinically, using targeted pharmacologic and genetic testing, that the gene-by-stress interactions that we have identified are really active and are not merely chance statistical associations? We have brought together a number of unique cohorts from completed lifestyle and intervention trials to begin to address these important scientific and clinical questions. In this Project 4, we will be studying the effects of stress-by-gene interactions on intervention effects and the converse in established cohorts from lifestyle and pharmacologic datasets; the effects of gene-by-stress interactions on adherence to exercise interventions; and the effects of gene-targeted pharmacologic agents on gene-by-stress effects on cardiometabolic phenotypes. Molecular data already collected will be provided to Project 3 to identify potential molecular pathways involved in the observed effects.